tbuckley/cabot-search huggingface dataset:
LGG-15. SINGLE-NUCLEUS AND BULK RNA SEQUENCING OF PEDIATRIC PILOCYTIC ASTROCYTOMAS REVEALS CNS LOCATION-ASSOCIATED TUMOR CELL AND MICROENVIRONMENTAL HETEROGENEITY
Authors: Julie A S Lammers, Jacob S Rozowsky, Mariëtte E G Kranendonk, Antoinette Y N Schouten-van Meeteren, Lisethe Meijer, Friso G Calkoen, Eelco W Hoving, Pieter Wesseling, Jasper van der Lugt, Lennart A Kester
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Pilocytic astrocytomas are the most common pediatric central nervous system (CNS) tumors. While the overall survival is generally favorable, a substantial part of the patients relapse, resulting in long-term complications. Additionally, pilocytic astrocytomas show limited genetic heterogeneity and are often driven by a single molecular event. The role of the tumor microenvironment (TME) in disease progression is yet unknown. Here, we aimed to delineate the composition of the tumor in pilocytic astrocytomas originating from different CNS locations. METHODS We collected 112 tumor samples, out of which a subset (n = 10) was used for single-nucleus RNA-sequencing (10X Genomics). These tumor samples originated from various CNS locations: posterior fossa (n = 64), supratentorial (n = 38) and spinal (n = 10). Clinical characteristics, DNA methylation profiles, whole exome/genome sequencing and bulk RNA sequencing data were available for most of these samples. RESULTS Single-nucleus RNA-sequencing revealed substantial heterogeneity amongst both tumor and TME cells, which mainly associated with tumor location. While a large proportion of tumor cells expressed gene signatures related to oligodendrocyte precursor cells (OLIG1/2, PDGFRA), a subset of tumor cells was characterized by high expression of astrocyte genes (AQP4, GFAP). Moreover, we defined multiple populations of lymphocytes and myeloid cells, with the latter constituting the vast majority of non-neoplastic cells. Deconvolution of the bulk RNA sequencing data showed heterogeneous involvement of the TME. Additionally, the relative abundances of TME cells varied considerably across CNS locations. We are currently correlating the relative proportions of tumor and TME cell populations with clinicopathological data. CONCLUSION Single-nucleus RNA-sequencing demonstrated transcriptional differences in both tumor cell states and TME cell populations, which associated with CNS location. Future research should elucidate the importance of the cellular composition of the tumor in pilocytic astrocytomas.
HGG-24. A NOVEL ONCOGENIC ROLE FOR MENIN IN GLIOMA
Authors: Yanhong Yang, Yuhki Saito, Elena Goldberg, Zaki Abou Mrad, Alexandra Giantini Larsen, Greta Ghita, Viviane Tabar
Journal: Neuro-Oncology (2023)

Abstract High-grade gliomas (HGGs) represent the most common subtype of primary malignant tumors from brain or spinal cord. With about 18 months overall survival time, HGGs is the leading cause of death from primary brain tumor. Survival outcomes have not improved significantly over the past two decades despite major research and therapeutic discovery efforts. Previous work from our lab suggested a role for menin in initiation and maintenance of pediatric high-grade glioma. Here we describe a critical oncogenic role of menin (encoded by the MEN1 gene) in maintaining HGGs proliferation. Using a panel of early passage HGG lines harboring diverse genomic alterations, we demonstrate that silencing of MEN1 blocks proliferation (60%-80%) of a subset (8/12) of HGGs, independent of their genomic alteration profile. An oncogenic role of menin has been described in MLL-rearrangement leukemia, where menin complexes with MLL to affect H3K4 trimethylation and activate leukemogenic genes. However, we found that the menin-MLL interaction is not associated with glioma. Instead, our mechanistic studies suggest that menin plays a critical role in maintaining H3K27 acetylation marks across the genome. Using immunoprecipitation and mass spectrometry, we identified HMGN1 (high mobility group nucleosome-binding domain 1 protein) as a putative novel menin partner. HMGN1 is a chromatin remodeling protein associated with chromatin accessibility and H3K27 acetylation. Transcriptional studies of patient-derived HGGs revealed that knockout of MEN1 and silencing of HMGN1 both resulted in broad repression of genes associated with proliferative tumor progenitor clusters. Ongoing work is aimed at therapeutic targeting by novel menin inhibitors. Our work demonstrates the role of epigenetic remodeling in controlling glioma proliferation and identifying novel therapeutic targets.
BIOL-22. CHILDREN’S BRAIN TUMOR NETWORK PRECLINICAL TUMOR MODELS DEVELOPMENT AND SHARING PLATFORM: COLLABORATIVE MODEL EMPOWERING PEDIATRIC BRAIN TUMOR DISCOVERY AND GLOBAL RESEARCH
Authors: Madison Hollawell, Valerie Baubet, David Beale, Luke Patterson, Ian Biluck, Ciana Anthony, Peeyush Goel, Christopher Beck, Poonam Sonawane, Crystal Griffin, Allison Stern, Peter Madsen, Jessica Foster, Jena Lilly, Jennifer Mason, Gerri Trooskin, Catherine Sullivan, Ashley Gehrand, Allison Morgan, Beth Frenkel, Kaitlin Lehmann, Lina Lopez, Thinh Nguyen, Ena Agbodza, Valeria Lopez-gil, Zeinab Helili, Alexa Plisiewicz, Noel Coleman, Yuankun Zhu, Xiaoyan Huang, Tatiana Patton, Stephanie Mcgrory, Kamnaa Arya, Ryan Velasco, Mariarita Santi, Angela Viaene, Phillip Storm, Mateusz Koptyra, Adam Resnick
Journal: Neuro-Oncology (2023)

Abstract Pediatric brain tumor preclinical development has suffered from the lack of robust in vitro and in vivo models that span the large number of brain tumor histologies. Opportunities for precision medicine approaches for solid and brain tumors are expanding, including immunotherapies, so it is essential to maximize access to preclinical models for studies of specificity, efficacy, and safety of treatments in ways that align patient models to patient samples and their clinical course. The Children’s Brain Tumor Network (CBTN) seeks to accelerate pediatric brain tumor research and discovery through support of the tumor model development program paired with molecularly characterized patient samples and longitudinal clinical data. This program focuses on the generation, characterization, and distribution of diverse models to investigators worldwide. Here we present currently available preclinical model resources comprising over 150 cell lines, organoids, and patient derived xenografts (PDX) developed and/or propagated at D3b at CHOP on behalf of CBTN. This platform maximizes the use of tumor tissue to generate a combination of cell lines, organoids and/or xenograft models grown in animals. To date, consortium-supported lines have been provided internationally to over 50 projects, encompassing basic biology and translational studies. Molecular data (whole genome sequencing and RNAseq) is currently available for over 80 models and a substantial portion of that cohort undergoes additional large-scale data generation and drug testing through collaborative work with Childhood Cancer Model Atlas, ProCan, and National Center for Advancing Translational Sciences. All models’ data are accompanied with patient molecular and clinical longitudinal information accessible through Kids First Data Resource, CAVATICA and PedcBio portals. This open-source repository model is an example of a unique research partnership supported by patients and their families and built with one mission – to accelerate therapeutic discovery for children suffering from brain tumors.
DIPG-48. DIPG THROUGH THE LOOKING GLASS
Authors: Sasi S Senga
Journal: Neuro-Oncology (2023)

Abstract Diffuse intrinsic pontine glioma (DIPG) has a peculiar pathogenesis with canonical Histone variants H3.1/H3.2 wherein Lysine 27 (H3K27) is substituted to methionine (H3K27M). It is restricted to pons and affects young children whereas non canonical H3.3 mutations result in tumours across the midline and affects older children. This discrepancy in the spatiotemporal distribution provides cues to target DIPG. Based on altered neuronal signalling which is a hallmark of cancer, a deeper understanding of neuron tumour interaction may unravel numerous new targets. One such target is light. The restriction of specific spectrum of light may hinder the progression and even the development of tumours in young children. It provides a lucrative therapeutic option which can be implemented merely by blocking a certain spectrum of light with glasses in an otherwise baffling disease. It warrants a deeper understanding of the light exposure on DIPG tumour progression.
DIPG-16. ACUTE VERSUS PROLONGED CONVECTION-ENHANCED DELIVERY OF ALISERTIB INTO H3 K27M-MUTANT MODELS OF DIFFUSE MIDLINE GLIOMA
Authors: Julian S Rechberger, Liang Zhang, Jizhi Ge, David J Daniels
Journal: Neuro-Oncology (2023)

Abstract Convection-enhanced delivery (CED) is a potentially promising strategy to administer therapeutics directly into the brainstem of children harboring H3 K27-altered diffuse midline glioma (DMG). While early-phase clinical trials have demonstrated the safety of this technique, efficacy has yet to be achieved. Here, we describe how different variations of CED may be exploited to extend survival in a DMG murine patient-derived orthotopic xenograft model. Either 1-day (8 µL/hr) or 7-day (1 µL/hr) continuous CED infusions were performed to deliver an equivalent volume of the aurora kinase inhibitor alisertib to the mouse brainstem. Bioluminescence and magnetic resonance images were acquired to monitor tumor progression, validate CED catheter positioning, and analyze infusion-related imaging changes. Both infusion regimens significantly prolonged survival versus control (median survival benefit of 6.5 and 8 days, p=0.03 and p=0.01, for 1-day and 7-day CED, respectively). Postmortem examination of brains revealed no signs of tissue necrosis, cavitary lesions, or cellular (inflammatory) infiltrate at the site of infusion. However, the tumor parenchyma surrounding the cannula tract was markedly hypocellular in treated animals. Alisertib induced a robust increase in H3 K27 trimethylation along with decreased H3 K27M and Ki-67. Our findings indicate that CED of alisertib is well tolerated and effective, in both the acute and prolonged setting, underscoring the potential of this approach in the management of DMG.
Hepaticogastrostomy as salvage treatment in a case of clinical failure of cholecystoduodenostomy due to tumoral obstruction of the cystic duct
Authors: Sergi Quintana-Carbo, Maria Puigcerver-Mas, Daniel Luna-Rodriguez, Albert Garcia-Sumalla, Sandra Maisterra, Joan B. Gornals
Journal: Endoscopy (2023)

A 75-year-old woman with a history of endometrial adenocarcinoma was admitted to the hospital with jaundice. A large retroperitoneal mass was diagnosed by imaging tests, and anatomopathological study confirmed a recurrence. An initial endoscopic ultrasound (EUS) was performed, showing a large mass infiltrating the duodenal wall and the pancreatic head, with both biliary and pancreatic ducts dilated. A transpapillary biliary drainage approach was unsuccessful due to tumor infiltration of the papilla.
MDB-08. THYROID HORMONES INHIBIT MEDULLOBLASTOMA PROGRESSION THROUGH INDUCING TUMOR CELL DIFFERENTIATION
Authors: Zeng-jie Yang, Yijun Yang, Allie Heller, Silvia Valdes Rives
Journal: Neuro-Oncology (2023)

Abstract Hypothyroidism is commonly detected in patients with medulloblastoma (MB), a pediatric brain tumor, which is generally considered as a treatment-related complication. Although reduced levels of thyroid hormone (TH) significantly correlate with poor survival of patients with MB, the possible link between TH signaling and MB pathogenicity is unknown. Here, we found that TH plays a critical role in MB pathogenicity through regulating the terminal differentiation of tumor cells. In the absence or with reduced levels of TH, unliganded TRα (a nuclear TH receptor) physically interacts with EZH2 to epigenetically repress the expression of NeuroD1, a transcription factor dictating terminal differentiation of neuronal progenitors and MB cells. However, TH reverses EZH2-mediated repression of NeuroD1 through interfering with the binding between EZH2 and TRα, thereby stimulating terminal differentiation of tumor cells and repressing MB pathogenicity. Moreover, TH promotes extensive differentiation and suppresses the proliferation of tumor cells from different molecular subgroups of MB5 including hedgehog (HH) group as well as group 3 (G3) MB, suggesting that TH-induced differentiation is not restricted by oncogenic mutations in tumor cells. Consequently, TH treatment significantly inhibits the in vivo growth of SHH- and G3-MB via stimulating tumor cell differentiation, with no induction of tumor cell apoptosis or death, indicating that TH signaling represents a novel therapeutic entry-point for broad treatment of MB. These findings elucidate the mechanisms underlying terminal differentiation of MB cells, establish an unprecedented association between TH signaling and MB progression. Our studies provide compelling evidence for a promising tumor therapeutic modality by promoting tumor cell differentiation.
Flat nodular lymphoid hyperplasia resembling “apple tree branches” in the colon
Authors: Stefan Mitev, Evelina G. Atanasova, Diana Kyoseva
Journal: Endoscopy (2023)

A 19-year-old woman with a history of adjustment disorder presented with abdominal pain, bloating, and chronic diarrhea. Colonoscopy revealed multiple flat whitish areas, less than 3 mm in diameter, diffusely distributed throughout the entire colon and rectum. These findings were prominent under narrow-band imaging (NBI) ([Fig. 1 a]) and more difficult to distinguish with white-light imaging ([Fig. 1 b]). The flat areas and the surrounding superficial vessels were described in the report as resembling "apple tree branches" ([Video 1]). Inspection of the terminal ileum was unremarkable, and esophagogastroduodenoscopy was unrevealing. Histologic examination of the colonic biopsy specimens showed nodules of benign lymphoid tissue with enlarged germinal centers and an intact mantle zone, consistent with a diagnosis of nodular lymphoid hyperplasia (NLH) ([Fig. 2]). Laboratory investigations and fecal calprotectin were within normal limits. Stool pathogen testing was negative. The patient was diagnosed with irritable bowel syndrome (IBS) and diffuse flat NLH.
TRLS-09. USE OF A PAN-PEPTIDE CHECKPOINT INHIBITOR IN THE TREATMENT OF CENTRAL NERVOUS SYSTEM TUMORS
Authors: Christopher Moertel, G Elizabeth Pluhar, Michael Olin
Journal: Neuro-Oncology (2023)

Abstract Immunotherapy has revolutionized clinical management of a select group of malignancies by offering a long-term, durable treatment response. Unfortunately, only a small percentage of brain cancers respond. The combination of multiple checkpoint inhibitors may result in serious immune-related adverse events. We have developed a Pan-Immune Checkpoint Ligand that simultaneously controls multiple immune checkpoints. The CD200 immune checkpoint modulates the immune system through a single inhibitory receptor (CD200R1) and multiple activation receptors (CD200ARs). We developed a peptide ligand, CD200AR-L, that targets the CD200ARs, which results in activation of the immune system and suppression of the inhibitory effects of CD200 and other immune checkpoints. Treatment of high-grade glioma in companion dogs with autologous tumor lysate vaccinations and CD200AR-L resulted in a two-year progression-free survival rate of 20% with no significant adverse events. We believe this response is due to the ability of CD200AR-L to modulate multiple immune checkpoints through shared signaling molecules in both the CD200 and PD-1/PD-L1 checkpoint pathways. Our preliminary data demonstrate that CD200R1 and PD-1 mediated immune checkpoint signaling is through SHIP1. CD200AR-L overcomes the immunosuppressive effects of the tumor-derived CD200 and PD-L1 by downregulating these checkpoints on both antigen-presenting cells (APC) and T-cells. CD200AR-L also downregulates PD-1 on APCs and inhibits the upregulation of PD-1 and CTLA4 on T cells. This translational research has led to the initiation of a phase I dose-escalation clinical trial for recurrent glioblastoma in adults (NCT04642937) and the writing of an IND for a pediatric HGG/DIPG trial.
DIPG-31. HIF-1A AND HIF-2A COMBINATORIAL TARGETING OR HOW TO REVERSE THEIR BALANCED ONCOGENIC IMPACT
Authors: Quentin Fuchs, Romain Vauchelles, Erika Cosset, Lucas Gorka, Benoit Lhermitte, Eric Guerin, Clémence Hubsch, Sophie Foppolo, Youssef Hibaoui, Anis Feki, Thibaut Wolf, Monique Dontenwill, Natacha ENTZ-WERLE
Journal: Neuro-Oncology (2023)

Abstract HIF-1a and HIF-2a are master regulators operating during tumor hypoxia. Few data are available on their role in pediatric high-grade gliomas (pHGGs), in which recent insights on metabolism and immunotolerance induction through hypoxia-driven mechanisms might opening the path to study further this process and their molecular actors. Our study investigated and confirmed the balanced dependency of both transcription factors in pHGGs at protein levels, but not in their transcriptional reprogramming. We also examined how HIF-1a and HIF-2a are operating during acute and chronic hypoxia in a spatiotemporal cell setting. HIF-1a was clearly correlated within pHGGs samples and models to acute and moderate hypoxia, whereas HIF-2a was associated to H3.3K27M mutant DIPG and chronic hypoxia. The impact of targeting both transcription factors in pHGG-derived models was on cell proliferative and invasive mechanisms, especially when studying this drug testing in engineered neural tissues. We might position those new targets as an innovative way to counterpart their hyperactivation in tumor core hypoxia and to propose them as an innovative approach interfering with cell-to-cell adhesion and synaptic interactions with normal brain cells.
Successful conservative management of a delayed perforation following gastric endoscopic submucosal dissection
Authors: Shoma Sawai, Kyosuke Tanaka, Tsuyoshi Beppu, Yuhei Umeda, Misaki Nakamura, Yasuhiko Hamada, Hayato Nakagawa
Journal: Endoscopy (2023)

An early gastric cancer was found on the gastric body in an 85-year-old man. Subsequently, an endoscopic submucosal dissection (ESD) was performed ([Fig. 1], [Video 1]). Although the muscle tissue in the post-ESD ulcer was injured, the ulcer closure was incomplete. The 20-mm lesion was resected en bloc in a 48-mm specimen. On postoperative day 1, the patient complained of epigastric pain and vomiting. Although the physical examination revealed no rebound tenderness, blood tests revealed a high white blood cell count. Computed tomography showed free air and inflammation of intra-abdominal fat in the area adjacent to the stomach ([Fig. 2], arrow). Endoscopy revealed a 15-mm diameter floating black area inside the post-ESD ulcer ([Fig. 3]). This area was diagnosed as a post-ESD perforation and its closure was attempted using an over-the-scope clip and reopenable endoclips with minimum carbon dioxide insufflation. Considering the fragile tissue around the perforation, the over-the-scope clip was deployed on the edge of the perforation. The perforation narrowed and was completely closed using seven additional endoclips ([Fig. 4]). After consulting the surgeons, we selected conservative management because of the patient's stability. On postoperative day 6, the post-ESD ulcer was reinforced with polyglycolic acid sheets and fibrin glue ([Fig. 5]). The patient resumed eating on postoperative day 8 and was discharged on postoperative day 12. Histopathologically, the resected specimen showed a well-differentiated adenocarcinoma confined to the shallow submucosa with negative margins.
ATRT-02. AN INFANTILE PINEAL EMBRYONAL TUMOR SHOWING PATHOLOGICAL FEATURES OF A CNS GANGLIONEUROBLASTOMA IN ADDITION TO SMARCA4 MUTATIONS AND THE METHYLATION PROFILING OF AN ATYPICAL TERATOID/RHABDOID TUMOR
Authors: Kohei Fukuoka, Atsuko Nakazawa, Junko Hirato, Sumihito Nobusawa, Toshikazu Itabashi, Yuki Arakawa, Yutaka Tanami, Koichi Ichimura, Jun Kurihara, Katsuyoshi Koh
Journal: Neuro-Oncology (2023)

Abstract Embryonal central nervous system tumors require genetic and epigenetic molecular analyses for further classification owing to the pathological, clinical, and molecular heterogeneity among these tumors. Here, we report a case of an infantile pineal tumor showing the pathological features of a CNS ganglioneuroblastoma; however, the specimen also contained SMARCA4 mutations and a methylation signature that is close to an atypical teratoid/rhabdoid tumor. A 2-year-old girl was referred to our hospital because of headache and dizziness presented with a pineal tumor and obstructive hydrocephalus. Radiologically, a large calcification was observed in the mass on head CT. The patient underwent tumor resection, and the pathological diagnosis was CNS ganglioneuroblastoma at that time. The specimen contained a variety of tumor cells, including undifferentiated embryonal cells, neurocytic cells, and ganglion cells embedded in a fibrillary matrix. The patient has been well for 5 years since they received multiagent chemotherapy and local proton irradiation. Subsequent genome-wide DNA methylation analysis revealed that the tumor was molecularly close to a sonic-hedgehog pathway-activated atypical teratoid/rhabdoid tumor. Genetic analysis also revealed SMARCA4 alterations in the splicing region of exons 10 and 34. This report indicates that genetic and epigenetic molecular approaches may facilitate elucidation of the clinical heterogeneity of CNS embryonal tumors, particularly the pathological appearance of CNS ganglioneuroblastomas.
DIPG-10. DELTA-24-RGDOX PROMOTES ANTITUMOR IMMUNE RESPONSE IN DMG MODELS
Authors: Virginia Laspidea, Iker Ausejo-Mauleon, Daniel de la Nava, Sara Nuin, Reyes Hernandez-Osuna, Javier Marco-Sanz, Daniel Palacios-Alonso, Candelaria Gomez-Manzano, Juan Fueyo, Marta Alonso
Journal: Neuro-Oncology (2023)

Abstract Diffuse Midline Gliomas (DMG) are very aggressive brain tumors that arise in the brainstem of children. The prognosis of these patients is still dismal, with an overall survival of less than one year. DMG tumors are poorly infiltrated by the immune system, and therefore in this project, we propose the use of the oncolytic adenovirus Delta-24-RGDOX to enhance the antitumor immune response. Delta-24-RGDOX is based on the Delta-24-RGD platform and incorporates the OX40 ligand (OX40L). The binding of OX40 to OX40L leads to the co-stimulation of CD4 and CD8 cells, generating effector and memory T cells. Therefore, the aim of this project is to improve the antitumor effect of the virus, providing a greater co-stimulation in the tumor. In vitro, Delta-24-RGDOX was able to efficiently infect and express viral proteins in human and murine DMG cell lines, and to cause cell death in a dose-dependent manner. Moreover, the virus expressed OX40L on the membrane of infected cells, which was functional and capable of activating CD8 T cells. Once we confirmed that the viral administration into DMG in vivo models was safe, we evaluated the therapeutic effect of the virus. We observed a significant survival increase after Delta-24-RGDOX treatment of a DMG model at early tumor stage (P=0.0033, median OS PBS 9 vs 12 days for virus treated mice) and in already stablished tumors (P=0.018, median OS PBS 9 vs 12.5 days for virus treated mice). Importantly, tumors from treated mice (7 days after treatment) displayed a significant increase of immune infiltration compared to controls. Moreover, splenocytes from Delta-24-RGDOX treated mice were also more activated. These data demonstrated that Delta-24-RGDOX expresses OX40L on infected cells, promoting the modulation of the tumor microenvironment and leading to an improved survival outcome in DMG models.